Molecules 2010, 15, 442-459; doi:10.3390/molecules15010442
Vitamin B6: A Molecule for Human Health?
Hanjo Hellmann * and Sutton Mooney
Washington State University, Abelson 435, P.O. Box 66224, Pullman, WA, USA
* Author to whom correspondence should be addressed; E-Mail: email@example.com.
Received: 5 November 2009; in revised form: 16 January 2010 / Accepted: 20 January 2010 /
Published: 20 January 2010
Abstract: Vitamin B6 is an intriguing molecule that is involved in a wide range of
metabolic, physiological and developmental processes. Based on its water solubility and
high reactivity when phosphorylated, it is a suitable co-factor for many biochemical
processes. Furthermore the vitamin is a potent antioxidant, rivaling carotenoids or
tocopherols in its ability to quench reactive oxygen species. It is therefore not surprising
that the vitamin is essential and unquestionably important for the cellular metabolism and
well-being of all living organisms. The review briefly summarizes the biosynthetic
pathways of vitamin B6 in pro- and eukaryotes and its diverse roles in enzymatic reactions.
Finally, because in recent years the vitamin has often been considered beneficial for human
health, the review will also sum up and critically reflect on current knowledge how human
health can profit from vitamin B6.
Keywords: vitamin B6; PDX; de novo; salvage; health
The B vitamins are a group of water soluble, chemically quite distinct compounds to which other
than vitamin B6, vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin or niacin amide), B5 (pantothenic
acid), B7 (biotin), B9 (folic acid), and B12 (various cobalamins) also belong . Historically, it was
believed that only one vitamin B existed with a critical function for maintenance of growth and health
and prevention of characteristic skin lesions in animals and human . However, with ongoing
research it became obvious that vitamin B actually comprised a group of compounds that was
collectively called the ‘vitamin B complex’.
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Vitamin B6 (vitB6 from here on) itself is an enzymatic co-factor required for more than 140
biochemical reactions including transaminations, aldol cleavages, α-decarboxylations, racemizations,
β- and γ- eliminations, and replacement reactions. Most of these reactions are related to amino acid
biosynthesis and degradation, but vitB6 is also involved in other processes including sugar and fatty
acid metabolism . It comprises a set of three different pyridine derivatives called pyridoxine (PN;
1), pyridoxal (PL; 2), and pyridoxamine (PM; 3). They differ in a variable group present at their 4-
position with PN carrying a hydroxymethyl group, and PL (2) and PM (3) having an aldehyde and an
aminomethyl group, respectively. Furthermore, all three B6 vitamers are phosphorylated by a kinase,
which is a requirement for their role as cofactors in enzymatic reactions (Scheme 1). While
pyridoxamine-5’-phosphate (PMP; 4) has been reported to function as a co-factor, it is pyridoxal 5’-
phosphate (PLP; 5) that is the biologically most active form [4,5].
A growing number of interesting and helpful new resources have been established in the last years
that focus primarily on vitB6 related issues. For example, an online database has been launched that
allows searching whole genomes for PLP-dependent enzymes, and which also provides information on
critical aspects such as the biochemical pathways requiring PLP (5) and the classification of PLP-
dependent enzymes (http://bioinformatics.unipr.it/cgi-bin/bioinformatics/B6db/home.pl) . In
addition, a database has been established that allows searching for mutated PLP-dependent enzymes in
various organisms (http://www.studiofmp.com/plpmdb/home.htm) .
2. Suggested Reaction Mechanisms of VitB6 for Amino Acid Metabolism
In most cases PLP (5) is covalently bound to the ε-amino group of a conserved lysine residue in the
active center of a PLP-dependent enzyme, with its 5’-phosphate group being buried in a conserved
phosphate-binding cup . It is suggested that reactions are initiated by the formation of a geminal
diamine intermediate between the aldehydic carbon atom of PLP (5) and an amino group of the
substrate. This is followed by its rapid breakdown and the formation of an external aldimine (Schiff
base) between PLP (5) and the substrate causing the release of the lysine residue of the enzyme from
PLP (5). From this point on subsequent reactions mainly depend on the specific, participating enzymes
that guide and modulate the next steps leading to e.g. racemisations, β- and γ- eliminations.
3. Three Different Biosynthetic Pathways for VitB6 Are Known
Three different pathways for vitB6 biosynthesis have been described which will be just briefly
summarized, as they were topics of other recent reviews [8,9]. In eubacteria like Escherichia coli, the
vitamin can be de novo synthesized by the concerted activities of the pyridoxine biosynthesis proteins
A and J (PdxA (EC 184.108.40.2062) and PdxJ (EC 220.127.116.11), respectively) which use 4-phospohydroxy-L-
threonine (4HPT; 6) and deoxyxylose 5’-phosphate (DXP; 7) to synthesize pyridoxine 5’-phosphate
(PNP; 8) (Scheme 1) [10–12]. In bacteria, archaea, and eukarya a second de novo pathway is known
that synthesizes PLP (5) from ribose 5’-phosphate (9) or ribulose 5’-phosphate (10), in combination
with either glyceraldehyde 3’-phosphate (11) or dihydroxyacetone phosphate (12) and glutamine (13)
(Scheme 1) [13–17].
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Scheme 1. The three known pathways for PLP biosynthesis: one salvage pathway, and
two de novo pathways, a DXP-dependent one and a DXP-independent one. Chemical
structures: (5) PLP; (7) deoxyxylulose 5’-phosphate, (6) 4-(phosphohydroxy)-L-
threonine; (11) glyceraldehyde 3’-phosphate; (12) dihydroxyacetone phosphate; (9)
ribose 5’-phosphate; (10) ribulose 5’-phosphate, (13) glutamine, (3) PM, (4) PMP, (1)
PN, (8) PNP, (2) PL.
Here two pyridoxine biosynthetic enzymes (PDX) are active: while PDX2 functions as a
glutaminase that deaminates glutamine to glutamate in order to supply nitrogen for the PLP
heterocycle, PDX1 arranges the final ring closure [18–24]. Because of a different sugar precursor used
for the biosynthesis of the vitamin, the de novo pathway from eubacteria is known as the DXP-
dependent pathway, while the other is the DXP-independent pathway . In addition to the two de
novo pathways, most organisms also have a salvage pathway that converts the different B6 vitamers to
PLP (5). This is achieved by the concerted activities of an oxidase, PDXH (EC 18.104.22.168), and a kinase,
PDXK (EC 22.214.171.124) (Scheme 1) [8,25]. Most animal organisms, including humans, have a salvage
Molecules 2010, 15
66. Vasdev, S.; Whalen, M.; Ford, C. A.; Longerich, L.; Prabhakaran, V.; Parai, S. Ethanol- and
threonine-induced hypertension in rats: a common mechanism. Can. J. Cardiol. 1995, 11, 807–
67. Vasdev, S.; Wadhawan, S.; Ford, C.A.; Parai, S.; Longerich, L.; Gadag, V. Dietary vitamin B6
supplementation prevents ethanol-induced hypertension in rats. Nutr. Metab. Cardiovasc. Dis.
1999, 9, 55–63.
68. Gloria, L.; Cravo, M.; Camilo, M.E.; Resende, M.; Cardoso, J.N.; Oliveira, A.G.; Leitao, C.N.;
Mira, F.C. Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol
consumption. Am. J. Gastroenterol. 1997, 92, 485–489.
69. Huber, K.H.; Rexroth, W.; Werle, E.; Koeth, T.; Weicker, H.; Hild, R. Sympathetic neuronal
activity in diabetic and non-diabetic subjects with peripheral arterial occlusive disease. Klin.
Wochenschr. 1991, 69, 233–238.
70. Cicila, G.T. Strategy for uncovering complex determinants of hypertension using animal models.
Curr. Hypertens. Rep. 2000, 2, 217–226.
71. MacKenzie, K.E.; Wiltshire, E.J.; Gent, R.; Hirte, C.; Piotto, L.; Couper, J.J. Folate and vitamin
B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics
2006, 118, 242–253.
72. Nakamura, S.; Li, H.; Adijiang, A.; Pischetsrieder, M.; Niwa, T. Pyridoxal phosphate prevents
progression of diabetic nephropathy. Nephrol. Dial. Transplant 2007, 22, 2165–2174.
73. Adrover, M.; Vilanova, B.; Munoz, F.; Donoso, J. Inhibition of glycosylation processes: the
reaction between pyridoxamine and glucose. Chem. Biodivers. 2005, 2, 964–975.
74. Nagore, E.; Insa, A.; Sanmartin, O. Antineoplastic therapy-induced palmar plantar
erythrodysesthesia ('hand-foot') syndrome. Incidence, recognition and management. Am. J. Clin.
Dermatol. 2000, 1, 225–234.
75. Taylor, B.V.; Oudit, G.Y.; Evans, M. Homocysteine, vitamins, and coronary artery disease.
Comprehensive review of the literature. Can. Fam. Physician 2000, 46, 2236–2245.
76. Matsubara, K.; Matsumoto, H.; Mizushina, Y.; Lee, J.S.; Kato, N. Inhibitory effect of pyridoxal
5'-phosphate on endothelial cell proliferation, replicative DNA polymerase and DNA
topoisomerase. Int. J. Mol. Med. 2003, 12, 51–55.
77. Bostom, A.G.; Carpenter, M.A.; Kusek, J.W.; Hunsicker, L.G.; Pfeffer, M.A.; Levey, A.S.;
Jacques, P.F.; McKenney, J. Rationale and design of the Folic Acid for Vascular Outcome
Reduction In Transplantation (FAVORIT) trial. Am. Heart J. 2006, 152, 448.
78. Menon, V.; Wang, X.; Greene, T.; Beck, G.J.; Kusek, J.W.; Selhub, J.; Levey, A.S.; Sarnak, M.J.
Homocysteine in chronic kidney disease: Effect of low protein diet and repletion with B vitamins.
Kidney Int. 2005, 67, 1539–1546.
79. Adrover, M.; Vilanova, B.; Frau, J.; Munoz, F.; Donoso, J. A comparative study of the chemical
reactivity of pyridoxamine, Ac-Phe-Lys and Ac-Cys with various glycating carbonyl compounds.
Amino Acids 2009, 36, 437–448.
80. Metz, T.O.; Alderson, N.L.; Thorpe, S.R.; Baynes, J.W. Pyridoxamine, an inhibitor of advanced
glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications.
Arch. Biochem. Biophys. 2003, 419, 41–49.
Molecules 2010, 15
81. Voziyan, P.A.; Metz, T.O.; Baynes, J.W.; Hudson, B.G. A post-Amadori inhibitor pyridoxamine
also inhibits chemical modification of proteins by scavenging carbonyl intermediates of
carbohydrate and lipid degradation. J. Biol. Chem. 2002, 277, 3397–3403.
82. Berger, M.; Gray, J.A.; Roth, B.L. The expanded biology of serotonin. Annu. Rev. Med. 2009, 60,
83. Matxain, J.M.; Padro, D.; Ristila, M.; Strid, A.; Eriksson, L.A. Evidence of high *OH radical
quenching efficiency by vitamin B6. J. Phys. Chem. B. 2009, 113, 9629–9632.
84. Belelli, D.; Harrison, N.L.; Maguire, J.; Macdonald, R.L.; Walker, M.C.; Cope, D.W.
Extrasynaptic GABAA receptors: form, pharmacology, and function. J. Neurosci. 2009, 29,
85. Hvas, A.M.; Juul, S.; Bech, P.; Nexo, E. Vitamin B6 level is associated with symptoms of
depression. Psychother. Psychosom. 2004, 73, 340–343.
86. Hoffmann, G.F.; Schmitt, B.; Windfuhr, M.; Wagner, N.; Strehl, H.; Bagci, S.; Franz, A. R.;
Mills, P.B.; Clayton, P.T.; Baumgartner, M.R.; Steinmann, B.; Bast, T.; Wolf, N.I.; Zschocke, J.
Pyridoxal 5'-phosphate may be curative in early-onset epileptic encephalopathy. J. Inherit. Metab.
Dis. 2007, 30, 96–99.
87. Lott, I.T.; Coulombe, T.; Di Paolo, R.V.; Richardson, E.P. Jr.; Levy, H.L. Vitamin B6-dependent
seizures: pathology and chemical findings in brain. Neurology 1978, 28, 47–54.
88. McCarty, M.F. High-dose pyridoxine as an 'anti-stress' strategy. Med. Hypotheses 2000, 54,
89. Leuendorf, J.E.; Genau, A.; Szewczyk, A.; Mooney, S.; Drewke, C.; Leistner, E.; Hellmann, H.
The Pdx1 family is structurally and functionally conserved between Arabidopsis thaliana and
Ginkgo biloba. FEBS J. 2008, 275, 960–969.
90. Kästner, U.; Hallmen, C.; Wiese, M.; Leistner, E.; Drewke, C. The human pyridoxal kinase, a
plausible target for ginkgotoxin from Ginkgo biloba. FEBS J. 2007, 274, 1036–1045.
91. Denslow, S.A.; Walls, A.A.; Daub, M.E. Regulation of biosynthetic genes and antioxidant
properties of vitamin B6 vitamers during plant defense responses. Physiol. Mol. Plant Path.
2005, 66, 244–255.
92. Bilski, P.; Li, M.Y.; Ehrenshaft, M.; Daub, M.E.; Chignell, C.F. Vitamin B6 (pyridoxine) and its
derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants. Photochem.
Photobiol. 2000, 71, 129–134.
93. Ehrenshaft, M.; Jenns, A.E.; Chung, K.R.; Daub, M.E. SOR1, a gene required for photosensitizer
and singlet oxygen resistance in Cercospora fungi, is highly conserved in divergent organisms.
Mol. Cell 1998, 1, 603–609.
94. Chen, H.; Xiong, L. Pyridoxine is required for post-embryonic root development and tolerance to
osmotic and oxidative stresses. Plant J. 2005, 44, 396–408.
95. Chumnantana, R.; Yokochi, N.; Yagi, T. Vitamin B6 compounds prevent the death of yeast cells
due to menadione, a reactive oxygen generator. Biochim. Biophys. Acta 2005, 1722, 84–91.
96. DiSorbo, D.M.; Wagner, R. Jr.; Nathanson, L. In vivo and in vitro inhibition of B16 melanoma
growth by vitamin B6. Nutr. Cancer 1985, 7, 43–52.
97. DiSorbo, D.M.; Nathanson, L. High-dose pyridoxal supplemented culture medium inhibits the
growth of a human malignant melanoma cell line. Nutr. Cancer 1983, 5, 10–15.
Molecules 2010, 15
98. Komatsu, S.; Yanaka, N.; Matsubara, K.; Kato, N. Antitumor effect of vitamin B6 and its
mechanisms. Biochim. Biophys. Acta 2003, 1647, 127–130.
99. Stolzenberg-Solomon, R.Z.; Albanes, D.; Nieto, F.J.; Hartman, T.J.; Tangrea, J.A.; Rautalahti,
M.; Sehlub, J.; Virtamo, J.; Taylor, P.R. Pancreatic cancer risk and nutrition-related methyl-
group availability indicators in male smokers. J. Natl. Cancer Inst. 1999, 91, 535–541.
100. Harbige, L.S. Nutrition and immunity with emphasis on infection and autoimmune disease. Nutr.
Health 1996, 10, 285–312.
101. Delport, R.; Ubbink, J.B.; Bosman, H.; Bissbort, S.; Vermaak, W.J. Altered vitamin B6
homeostasis during aminophylline infusion in the beagle dog. Int. J. Vitam. Nutr. Res. 1990, 60,
102. Delport, R.; Ubbink, J.B.; Serfontein, W.J.; Becker, P.J.; Walters, L. Vitamin B6 nutritional
status in asthma: the effect of theophylline therapy on plasma pyridoxal-5'-phosphate and
pyridoxal levels. Int. J. Vitam. Nutr. Res. 1988, 58, 67–72.
103. van den Berg, H.; Louwerse, E.S.; Bruinse, H.W.; Thissen, J.T.; Schrijver, J. Vitamin B6 status
of women suffering from premenstrual syndrome. Hum. Nutr. Clin. Nutr. 1986, 40, 441–450.
104. Bernstein, A.L. Vitamin B6 in clinical neurology. Ann. N. Y. Acad. Sci. 1990, 585, 250–260.
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